Abstract:

A pharmaceutical composition comprises multiparticulates comprising a
melt-congeal core and a solid amorphous dispersion layer of a poorly
water soluble drug and polymer. The multiparticulates are suitable for
improving bioavailability of poorly water soluble drugs. The melt-congeal
cores facilitate application of the solid amorphous dispersion layer, and
allow incorporation of additional optional components to the core so as
to adjust the release of drug from the multiparticulate.

Claims:

1-20. (canceled)

21. A pharmaceutical composition comprising multiparticulates, each of
said multiparticulates comprising:(a) a melt-congeal core surrounded by a
solid amorphous dispersion layer comprising a drug and a polymer, wherein
at least a major portion of said drug in said solid amorphous dispersion
layer is amorphous and wherein at least a portion of said solid amorphous
dispersion layer is in the form of a solid solution;(b) said melt-congeal
core comprising a matrix material present in an amount of at least 30 wt
% of said core, said matrix material being solid at 25.degree. C. and
having a melt temperature of less than 200.degree. C., wherein said
matrix material is selected from the group consisting of waxes, long
chain alcohols, fatty acid esters, glycolized fatty acid esters,
phosphoglycerides, polyoxyethylene alkyl ethers, long chain carboxylic
acids, sugar alcohols, and mixtures thereof.

29. A process for making a pharmaceutical composition of multiparticulates
comprising the steps:(a) forming a molten mixture comprising at least 30
wt % of a matrix material;(b) atomizing said molten mixture of step (a)
to form droplets;(c) congealing said droplets of step (b) to form solid
cores;(d) forming a spray solution comprising a solvent, a poorly water
soluble drug and a polymer; and(e) spray-coating said spray solution of
step (d) onto said cores of step (c) to form a solid amorphous dispersion
layer comprising said poorly water soluble drug and said polymer
surrounding said core, wherein at least a major portion of said drug in
said solid amorphous dispersion layer is amorphous and wherein at least a
portion of said solid amorphous dispersion layer is in the form of a
solid solution.

30. The process of claim 29 further comprising the step of adding an
additional component to said molten mixture of step (a) selected from the
group consisting of a swelling agent, said drug, a second different drug,
a dissolution-enhancer, and a dissolution-inhibitor.

Description:

[0002]It is well known that poorly water soluble drugs may be formulated
as a solid amorphous dispersion of a drug in a polymer to improve the
bioavailability of poorly soluble drugs. Preferred solid amorphous
dispersions are formed by spray drying. Such solid amorphous dispersions
are also referred to as molecular dispersions. A drawback of such spray
dried dispersions is that the particles resulting from the spray-drying
process are often very small (typically less than 100 microns in
diameter) and have high specific volume (typically greater than 3
cm3/g). These properties make spray dried dispersions difficult to
handle, and therefore complicate formulation of such dispersions into
dosage forms suitable for oral delivery.

[0003]One approach to increasing the size and density of such solid
amorphous dispersions is to spray-coat the drug and polymer onto an inert
core. For example, the drug and polymer may be spray-coated onto an inert
sugar sphere or microcrystalline cellulose. See, e.g., WO 02/38128.
However, spray-coating such materials presents several problems. First,
conventional sugar cores and the like are friable. Such materials have a
tendency to break apart into smaller pieces in the fluid bed during the
coating process. The fine material can be swept up into the gas stream,
resulting in an inefficient coating process. In addition, the average
core size tends to decrease as the coating time increases, resulting in a
size distribution that changes over time. Since the release rate of the
drug is dependent on the surface area of the multiparticulate, the
dissolution rate of the spray-coated multiparticulates will be a function
of the coating time. This can lead to non-reproducible dissolution rates
from spray-coated multiparticulates due to slight differences in coating
conditions from batch to batch. Conventional sugar cores and the like
also tend to have rough, irregular surfaces, which can be difficult to
coat uniformly.

[0004]Another problem associated with spray-coating on to conventional
excipients is that the drug dissolution rate from such multiparticulates
can be slow. Dissolution rate is dependent on the size of the
multiparticulate and composition of the amorphous dispersion layer. It is
desired to form small cores to coat, since smaller multiparticulates
generally have higher dissolution rates. However, conventional sugar
cores and the like are difficult to obtain in small sizes. In addition,
surface irregularities tend to increase as the size of these particles
decrease, making uniform coating difficult.

[0005]Another problem associated with sugar cores is that the sugar can
act as an osmogen. When the particle is administered to an aqueous use
environment, the particle can absorb water. The sugar core may rapidly
absorb water, causing the multiparticule to rupture and prematurely
release the drug.

[0006]What is therefore desired is a composition comprising a solid
amorphous dispersion of drug and polymer coated onto a small, smooth
inert core to provide a multiparticulate that has a size and density that
facilitates processing of the dispersion into oral dosage forms, and that
also allows the drug dissolution rate and release rate of the drug to be
adjusted.

BRIEF SUMMARY OF THE INVENTION

[0007]In a first aspect, a pharmaceutical composition comprises
multiparticulates. The multiparticulates comprise a melt-congeal core
surrounded by a solid amorphous dispersion layer comprising a drug and a
polymer, wherein at least a major portion of the drug in the solid
amorphous dispersion layer is amorphous and wherein at least a portion of
the solid amorphous dispersion layer is in the form of a solid solution.
The melt-congeal core comprises a matrix material present in an amount of
at least 30 wt % of the core. The matrix material is solid at 25°
C. The matrix material has a melt temperature of less than 200° C.
The matrix material is selected from the group consisting of waxes, long
chain alcohols (C12 or greater), fatty acid esters, glycolized fatty
acid esters, phosphoglycerides, polyoxyethylene alkyl ethers, long chain
carboxylic acids (C12 or greater), sugar alcohols, and mixtures
thereof.

[0015]In another embodiment, the matrix material is selected from the
group consisting of fatty acids esters, waxes, long-chain alcohols,
ethoxylated fatty acid esters, long-chain carboxylic acids, and mixtures
thereof, and the polymer is selected from the group consisting of
hydroxypropyl methyl cellulose, and hydroxypropyl methyl cellulose
acetate succinate.

[0023]In another aspect of the invention, a process for making a
pharmaceutical composition of multiparticulates comprises the steps:
[0024](a) forming a molten mixture comprising at least 30 wt % of a
matrix material, the matrix material being selected from the group
consisting of waxes, long chain alcohols (C12 or greater), fatty
acid esters, glycolized fatty acid esters, phosphoglycerides,
polyoxyethylene alkyl ethers, long chain carboxylic acids (C12 or
greater), sugar alcohols, and mixtures thereof; [0025](b) atomizing the
molten mixture of step (a) to form droplets; [0026](c) congealing the
droplets of step (b) to form solid cores; [0027](d) forming a spray
solution comprising a solvent, a poorly water soluble drug and a polymer;
and [0028](e) spray-coating the spray solution onto the cores of step (c)
to form a solid amorphous dispersion layer comprising the poorly water
soluble drug and the polymer surrounding the core, wherein at least a
major portion of the drug in the solid amorphous dispersion layer is
amorphous and wherein at least a portion of the solid amorphous
dispersion layer is in the form of a solid solution.

[0029]By "multiparticulates" is meant a plurality of small particles
having a volume-weighted mean diameter of from about 10 microns up to
about 3 mm. Unless otherwise noted, the size of the multiparticulates
refers to the diameter of the core and surrounding solid amorphous
dispersion layer, but excludes any optional exterior coating applied over
the solid amorphous dispersion layer. The multiparticulates preferably
have an average diameter of less than 500 microns, and more preferably
less than about 300 microns.

[0030]The use of a spray-coated solid amorphous dispersion on a
melt-congeal core provides a number of advantages. First, the
melt-congeal cores are less friable than conventional sugar cores. The
melt-congeal cores do not break apart into smaller particles as quickly
as sugar cores during the coating process, resulting in multiparticulates
with more uniform size distributions and less batch to batch variance.
The melt-congeal cores are also smooth and round, making the cores easier
to coat relative to sugar cores and the like.

[0031]Second, the melt-congeal cores can be formed into very small
particles. Melt-congeal cores can be made with a volume weighted diameter
of less than 100 microns. This allows multiparticulates to be formed at
small size with a rapid dissolution rate. Moreover, the melt-congeal
cores remain smooth and round even at small size, in contrast to small
sugar cores which become increasingly irregular and difficult to coat as
the size decreases.

[0032]Third, many of the materials used to form melt-congeal cores also
tend to be hydrophobic. Thus, in contrast to water soluble core materials
such as sugar, the cores will not absorb water. The release of the drug
from the cores is therefore not affected by the core material. In
addition, many of the materials used to form the core are biodegradable.
Thus, the melt-congeal cores may be used in dosage forms in which
non-biodegradable materials would not be appropriate, such as parenteral
dosage forms.

[0033]Finally, the melt-congeal cores allow incorporation of other
materials into the core that can be used to adjust the dissolution rate
of the drug, or to alter the release rate of the drug from the
multiparticulates. For example, the core may contain excipients such as
swelling agents to rupture the core to increase dissolution of the drug.
Alternatively, the matrix material may contain additional drug, or a
different drug, to allow modification of the drug release profile. Such
cores may release the drug quickly, or may provide slow release of the
drug.

[0034]The foregoing and other objectives, features, and advantages of the
invention will be more readily understood upon consideration of the
following detailed description of the invention.

[0036]FIG. 2 is a cross-sectional schematic of another embodiment
comprising drug in the core of the multiparticulate.

[0037]FIG. 3 is a cross-sectional schematic of another embodiment
comprising a swelling agent in the core of the multiparticulate.

[0038]FIG. 4 is a cross-sectional schematic of another embodiment
comprising a coating surrounding the exterior of the multiparticulate.

[0039]FIG. 5 is a cross-sectional schematic of another embodiment
comprising a swelling agent in the core of the multiparticulate and
surrounded by an exterior coating.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0040]Referring to the drawings, there is shown in FIG. 1 a
cross-sectional schematic of a multiparticulate 1 of the invention,
comprising a melt-congeal core 10 comprising a matrix material 12
surrounded by a solid amorphous dispersion layer 20. The melt-congeal
core may comprise other optional excipients or materials, such as a
swelling agent, drug or a second drug, or dissolution enhancers. The
solid amorphous dispersion layer comprises a drug and a polymer, in which
at least a major portion of the drug is amorphous and dispersed in the
polymer. The multiparticulates may also comprise an optional exterior
coating surrounding the solid amorphous dispersion layer. The
melt-congeal cores, solid amorphous dispersion layers, optional exterior
coatings, and processes for forming the multiparticulates are described
in more detail below.

Melt-Congeal Core

Matrix Materials

[0041]As shown in FIGS. 1-5, the melt-congeal core 10 comprises a matrix
material 12. The matrix material serves two functions. First, the matrix
material allows formation of relatively smooth, round cores that are
amenable to coating. Second, the matrix material binds the optional
excipients and/or drugs that may be incorporated into the core. The
matrix material has the following physical properties: a sufficiently low
viscosity in the molten state to form multiparticulates, as detailed
below, and rapidly congeals to a solid when cooled below its melting
point. For those multiparticulates incorporating drug in the core, the
matrix preferably has a melting point below that of the melting point or
decomposition point of the drug, and does not substantially dissolve the
drug.

[0042]The melt-congeal cores consist essentially of a continuous phase of
matrix material and optionally other excipients, with optional drug
particles and optional swelling agent particles encapsulated within.
Because of this, a sufficient amount of matrix material must be present
to form smooth cores that are large enough to coat. In the case of cores
containing solid particles, such as drug or swelling agent, the core must
contain a sufficient amount of matrix material to encapsulate the drug
and swelling agent to form relatively smooth and spherical cores, which
are more easily coated by conventional spray-coating processes than
irregularly-shaped ones. The matrix material may be present in the core
from at least about 30 wt %, at least about 50 wt %, at least about 70 wt
%, at least about 80 wt %, at least about 90 wt %, and up to 100 wt %
based on the mass of the uncoated core.

[0043]In order to form small, smooth round cores, the matrix material must
be capable of being melted and then atomized. The matrix material or
mixture of materials is solid at 25° C. However, the matrix
material melts, or is capable of melting with the addition of an optional
processing aid, at a temperature of less than 200° C. so as to be
suitable for melt-congeal processing described below. Preferably, the
matrix material has a melting point between 50° C. and 150°
C. Although the term "melt" generally refers to the transition of a
crystalline material from its crystalline to its liquid state, which
occurs at its melting point, and the term "molten" generally refers to
such a crystalline material in its fluid state, as used herein, the terms
are used more broadly. In the case of "melt," the term is used to refer
to the heating of any material or mixture of materials sufficiently that
it becomes fluid in the sense that it may be pumped or atomized in a
manner similar to a crystalline material in the fluid state. Likewise
"molten" refers to any material or mixture of materials that is in such a
fluid state.

[0050]In one embodiment, the matrix material is hydrophobic and poorly
water soluble. Exemplary matrix materials that are hydrophobic include
waxes and fatty acid esters.

Drug in Core

[0051]In another embodiment as illustrated in FIG. 2, the multiparticulate
2 comprises a core 10 containing a drug 14. The drug in its undispersed
state may be either crystalline or amorphous. The core may contain drug
in an amount of up to about 70 wt % based upon the total mass of the
uncoated core. In one embodiment, the amount of drug in the core may
range from 1 to 50 wt %, and more preferably from 5 to 40 wt %, and still
more preferably from 10 to 30 wt % based on the mass of the uncoated
core.

[0052]For drugs which are crystalline within the core, the drug in the
core is preferably "substantially crystalline," meaning that at least 70
wt % of the drug is in the crystalline state. More preferably the drug is
at least 80 wt % crystalline, and most preferably at least 90 wt %. In
addition, the drug should have a low solubility in the molten matrix
material. Dissolution of the drug in the matrix material can reduce the
crystallinity of the drug in the finished core and compromise the drug's
chemical and physical stability. The drug should have a solubility in the
molten matrix material of less than about 30 wt %, more preferably less
than about 20 wt %, and even more preferably less than about 10 wt %.

[0053]Alternatively, the drug in the core may be amorphous. The drug may
either be present as pure amorphous drug, or may be present as particles
of solid amorphous dispersion of drug in a matrix.

[0054]In those embodiments containing crystalline drug in the core, the
matrix material should have a melting point below that of the melting
point or decomposition point of the drug. By "decomposition point" of the
drug is meant the temperature at which the drug decomposes. By selecting
a matrix material that has a melt temperature below the melting point or
decomposition point of the drug, a molten mixture may be formed at a
temperature below that of the melting point of the drug. This allows the
drug to remain in its native state while being formed into cores. For
crystalline drugs, this means the drug remains in its original
crystalline state without melting or changing to another crystalline
form. Preferably, the matrix material becomes molten at a temperature
that is 10° C. less than the melting point of the drug, more
preferably at least 20° C. less than the melting point or
decomposition point of the drug, and even more preferably at least
30° C. less than the melting point or decomposition point of the
drug.

Swelling Agent

[0055]In another embodiment illustrated in FIG. 3, the multiparticulate 3
comprises a core 10 containing a water-swellable swelling agent 16 that
expands upon contact with aqueous fluids. The swelling agent 16 is
preferably present as a separate phase from the matrix material 12. The
swelling agent may be present in an amount of from 1 to 40 wt %, more
preferably from 5 to 35 wt %, and most preferably from 10 to 25 wt %
based upon the mass of the uncoated core.

[0056]The first requirement of the swelling agent is that it is highly
swelling. As the core imbibes water, the swelling agent must expand a
sufficient amount to rupture the core. Preferably, the swelling agent,
when contacted with aqueous gastric or simulated gastric fluid, can
expand in volume such that its swelling ratio is at least about 2, more
preferably at least about 3.5, and even more preferably at least about 5.

[0057]The following in vitro test may be used to determine the "swelling
ratio" of water-swellable materials. The swelling agent is compressed
into a compact using a 13/32-inch die, the compact having a strength
ranging from 3 to 16 Kp/cm2. The compact is then placed into a glass
cylinder of approximately the same inside diameter as the compact and the
volume of the compact is determined. Next, the glass cylinder is filled
with simulated gastric buffer consisting of 0.01 M HCl and 0.12 M NaCl in
deionized water. The glass cylinder and test media are all equilibrated
at a constant temperature of 37° C. The volume of the compact is
determined at several time intervals. The ratio of the volume of the
compact after reaching a constant height to that of the volume of the dry
compact is the swelling ratio, or swelling factor, of the swelling agent.

[0058]In addition, the swelling agent should swell rapidly. Rapid swelling
is desired for two reasons. First, the multiparticulate should release
the drug quickly. Therefore, swelling should be fast enough so that the
core ruptures. Second, for multiparticulates comprising a water insoluble
exterior coating 50 surrounding the drug layer 20 (as in FIG. 5), rapid
swelling is often necessary to rupture the coating. If the swelling agent
swells too slowly, the insoluble coating may slowly swell and expand
rather than rupture. Alternatively, the components of the core may
permeate through openings in the exterior coating, thus relieving the
internal pressure within the core. Using the test described above, the
rate at which swelling occurs may be determined. Preferably, the swelling
agent reaches a swelling ratio of at least about 2 in the simulated
gastric buffer within one hour, more preferably within about 30 minutes,
and most preferably within about 15 minutes.

[0059]Finally, the swelling agent should also be such that it may be
blended with the molten matrix material (described below) to form a
flowable suspension. The swelling agent is preferably present as a
separate phase in the core, so that when the core imbibes water, the
swelling agent swells and ruptures the coating. Preferably, the swelling
agent does not dissolve in the molten matrix. Thus, when the cores are
formed using a melt method, the swelling agent remains as a solid
suspended in the molten matrix. If the swelling agent does dissolve, it
should phase separate into large domains of relatively pure swelling
agent when the core congeals.

[0060]Exemplary swelling agents that are both highly swelling and swell
rapidly include polymers such as sodium starch glycolate (commercially
available as EXPLOTAB from Edward Mendell Co.), croscarmellose sodium
(commercially available as AC-DI-SOL from FMC Corporation of
Philadelphia, Pa.), and crospovidone. These polymers also are capable of
remaining as a separate solid phase in a molten matrix.

Additional Core Excipients

[0061]The core may also contain a variety of other excipients, present in
the core in an amount of from 0 to 40 wt %, based upon the mass of the
uncoated core.

[0062]One preferred excipient is a dissolution enhancer, which may be used
to increase the rate of water uptake by the core and consequent expansion
of the swelling agent. The dissolution enhancer is a different material
than the matrix material. The dissolution enhancer may be in a separate
phase or a single phase with the matrix material. Preferably, at least a
portion of the dissolution enhancer is phase-separated from the matrix
material. As shown in FIG. 3, the optional dissolution-enhancer 18 is
present as a separate phase in the matrix material 12. As water enters
the core 10, the dissolution-enhancer dissolves, leaving channels which
allow water to more rapidly enter the core to cause the swelling agent 16
to expand.

[0063]In general, dissolution enhancers are amphiphilic compounds and are
generally more hydrophilic than the matrix materials. Examples of
dissolution enhancers include: surfactants such as poloxamers, docusate
salts, polyoxyethylene castor oil derivatives, polysorbates, sodium
lauryl sulfate, and sorbitan monoesters; sugars, such as glucose,
xylitol, sorbitol and maltitol; salts, such as sodium chloride, potassium
chloride, lithium chloride, calcium chloride, magnesium chloride, sodium
sulfate, potassium sulfate, sodium carbonate, magnesium sulfate and
potassium phosphate; and amino acids, such as alanine and glycine; and
mixtures thereof. A preferred surfactant-type dissolution-enhancer is a
poloxamer (commercially available as the LUTROL or PLURONIC series from
BASF Corp.).

[0064]The core may also contain other optional excipients, such as agents
that inhibit or delay the release of drug from the multiparticulates.
Such dissolution-inhibiting agents are generally hydrophobic and include
dialkylphthalates such as dibutyl phthalate, and hydrocarbon waxes, such
as microcrystalline wax and paraffin wax.

[0065]Another useful class of excipients comprises materials that may be
used to adjust the viscosity of the molten feed used to form the cores.
Such viscosity-adjusting excipients will generally make up 0 to 25 wt %
of the core. The viscosity of the molten feed is a key variable in
obtaining cores with a narrow particle size distribution. For example,
when a spinning-disk atomizer is employed, it is preferred that the
viscosity of the molten mixture be at least about 1 cp and less than
about 10,000 cp, more preferably at least 50 cp and less than about 1000
cp. If the molten mixture has a viscosity outside these preferred ranges,
a viscosity-adjusting agent can be added to obtain a molten mixture
within the preferred viscosity range. Examples of viscosity-reducing
excipients include stearyl alcohol, cetyl alcohol, low molecular weight
polyethylene glycol (i.e., less than about 1000 daltons), isopropyl
alcohol, and water. Examples of viscosity-increasing excipients include
microcrystalline wax, paraffin wax, synthetic wax, high molecular weight
polyethylene glycols (i.e., greater than about 5000 daltons), ethyl
cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose,
methyl cellulose, silicon dioxide, microcrystalline cellulose, magnesium
silicate, sugars, and salts.

[0066]For those embodiments containing a drug in the core, other
excipients may be added to adjust the release characteristics of the drug
from the cores. For example, an acid or base may be included in the
composition to modify the rate at which drug is released in an aqueous
use environment. Examples of acids or bases that can be included in the
composition include citric acid, adipic acid, malic acid, succinic acid,
tartaric acid, di- and tribasic sodium phosphate, di- and tribasic
calcium phosphate, mono-, di-, and triethanolamine, sodium bicarbonate
and sodium citrate dihydrate. Such excipients may make up 0 to 25 wt % of
the core, based on the total mass of the core.

[0067]Still other excipients may be added to improve processing, such as
excipients to reduce the static charge on the cores or to reduce the
melting temperature of the matrix material. Examples of such anti-static
agents include talc and silicon dioxide. Flavorants, colorants, and other
excipients may also be added in their usual amounts for their usual
purposes. Such excipients may make up 0 to 25 wt % of the core, based on
the total mass of the core.

[0068]In one embodiment, the uncoated melt-congeal core components are
present in the following amounts, based upon the total mass of the
uncoated core:

[0069](i) matrix material from 80 to 100 wt %; and

[0070](ii) optional excipients from 0 to 20 wt %.

[0071]In another embodiment, the uncoated core components are present in
the following amounts, based upon the total mass of the uncoated core:
[0072](i) matrix material from 30 to 90 wt %, more preferably 50 to 80 wt
%; [0073](ii) drug up to 70 wt %, more preferably from 1 to 50 wt %,
still more preferably from 5 to 40 wt %, and most preferably from 10 to
30 wt %; and [0074](ii) optional dissolution enhancer from 0 to 20 wt %,
more preferably 2 to 15 wt %.

[0075]In another embodiment, the uncoated core components are present in
the following amounts, based upon the total mass of the uncoated core:
[0076](i) matrix material from 30 to 90 wt %, more preferably 50 to 80 wt
%; [0077](ii) optional dissolution enhancer from 0 to 20 wt %, more
preferably 2 to 15 wt %; and [0078](iii) swelling agent from 1 to 40 wt
%, more preferably from 5 to 35 wt %, and most preferably from 10 to 25
wt %.

[0079]In another embodiment, the core contains the same drug as in the
solid amorphous dispersion layer. The core provides slow release of the
drug. The matrix material may be poorly water soluble, such as a wax or
fat. Alternatively, the core may further comprise dissolution-inhibiting
agents. Such an embodiment may provide immediate release of the drug from
the solid amorphous dispersion layer, and controlled release of the drug
from the core.

[0080]In another embodiment, the core contains the same drug as in the
solid amorphous dispersion layer. The core provides fast release of the
drug. The matrix material may be water soluble, such as a water soluble
polymer or polyol. Alternatively, the core may further comprise
dissolution-enhancing agents. Such an embodiment may provide immediate
release of the drug from the solid amorphous dispersion layer, and
relatively fast release of the drug from the core (albeit at a somewhat
slower rate than dissolution of the drug from the solid amorphous
dispersion layer).

[0081]In another embodiment, the core contains a second drug that is
different than the drug in the solid amorphous dispersion layer. The core
provides slow release of the second drug. The matrix material may be
poorly water soluble, such as a wax or fat. Alternatively, the core may
further comprise dissolution-inhibiting agents. Such an embodiment may
provide immediate release of the drug from the solid amorphous dispersion
layer, and controlled release of the second drug from the core.

[0082]In another embodiment, the core contains a second drug that is
different than the drug in the solid amorphous dispersion layer. The core
provides fast release of the second drug. The matrix material may be
water soluble, such as a water soluble polymer or polyol. Alternatively,
the core may further comprise dissolution-enhancing agents. Such an
embodiment may provide immediate release of the drug from the solid
amorphous dispersion layer, and relatively fast release of the second
drug from the core.

Forming the Cores

[0083]The process used to form the cores comprises the steps of (a)
forming a molten mixture comprising the matrix material and the other
optional core components, (b) atomizing the molten mixture of step (a) to
form droplets, and (c) congealing the droplets from step (b) to form
cores. The steps of forming a molten mixture and atomizing may be
performed sequentially or simultaneously.

[0084]The matrix material and other optional core components are combined
to form a molten mixture. As previously noted, "molten mixture" refers to
a mixture that is treated by heat, pressure or shear forces to the point
that the mixture becomes sufficiently fluid that the mixture may be
formed into droplets or atomized. Generally the mixture is molten in the
sense that it will flow when subjected to one or more forces such as
pressure, shear, and centrifugal force, such as that exerted by a
centrifugal or spinning-disk atomizer. Thus, the mixture may be
considered "molten" when the mixture, as a whole, is sufficiently fluid
that it may be atomized.

[0085]For those embodiments in which the core contains a crystalline drug,
the temperature of the molten mixture is maintained below that of the
melting point or decomposition point of the drug but sufficiently high to
form the molten mixture. In addition, the temperature of the molten
matrix should be sufficiently low so that the solubility of the drug in
the matrix material is less than 30 wt %.

[0086]Virtually any process may be used to form the molten mixture. A
preferred method involves heating the matrix material in a tank until it
is fluid and then adding the drug and swelling agent. Generally, the
matrix material is heated to a temperature of about 10° C. or more
above the temperature at which it becomes fluid. Alternatively, both the
drug and the matrix material may be added to the tank and the mixture
heated until the molten mixture has become fluid.

[0087]Once the molten mixture has become fluid and the drug has been
added, the mixture is mixed to ensure that any optional drug or excipient
added to the matrix material is substantially uniformly distributed
therein.

[0088]An alternative method of forming the molten mixture is by an
extruder. By "extruder" is meant a device or collection of devices that
creates a molten extrudate by heat and/or shear forces and/or produces a
uniformly mixed extrudate from a solid and/or liquid (e.g., molten) feed.
Such devices include, but are not limited to single-screw extruders and
twin-screw extruders, including co-rotating, counter-rotating,
intermeshing, and non-intermeshing extruders. The molten mixture may
optionally be directed to an accumulation tank, before being directed to
a pump, which directs the molten mixture to an atomizer. Optionally, an
in-line mixer may be used before or after the pump to ensure the molten
mixture is substantially homogeneous. In each of these extruders the
molten mixture is mixed to form a uniformly mixed extrudate. Such mixing
may be accomplished by various mechanical and processing means, including
mixing elements, kneading elements, and shear mixing by backflow. Thus,
in such devices, the composition is fed to the extruder, which produces a
molten mixture that can be directed to the atomizer.

[0089]In one embodiment, the composition is fed to the extruder in the
form of a solid powder. The powdered feed can be prepared using methods
well known in the art for obtaining powdered mixtures with high content
uniformity. See Remington's Pharmaceutical Sciences (16th ed. 1980).

[0090]To aid in formation of the molten mixture, a processing aid may be
added. Some matrix materials, such as sugar alcohols such as mannitol or
erythritol, are capable of becoming molten at a temperature below their
melting point in the presence of a processing aid such as water. The
processing aid may act to depress the melting point of the matrix
material, partially dissolve the matrix material, or both, thus allowing
the matrix material to become molten. The processing aid may evaporate
during formation of the melt-congeal cores, so that the resulting
melt-congeal core contains only the matrix material but not the
processing aid.

[0091]Once the molten mixture has been formed, it is delivered to an
atomizer that breaks the molten mixture, or feed, into small droplets.
Any suitable method can be used to deliver the molten mixture to the
atomizer, including the use of pumps and various types of pneumatic
devices such as pressurized vessels or piston pots. When an extruder is
used to form the molten mixture, the extruder itself can be used to
deliver the molten mixture to the atomizer. Typically, the molten mixture
is maintained at an elevated temperature while delivering the mixture to
the atomizer to prevent solidification of the mixture and to keep the
molten mixture flowing.

[0092]Atomization may be conducted in a number of ways, including (1) by
"pressure" or single-fluid nozzles; (2) by two-fluid nozzles; (3) by
ultrasonic nozzles; (4) by mechanical vibrating nozzles; or (5) by
centrifugal or spinning-disk atomizers. Detailed descriptions of
atomization processes can be found in Lefebvre, Atomization and Sprays
(1989) and in Perrys Chemical Engineers' Handbook (7th Ed. 1997), the
disclosures of which are incorporated herein by reference.

[0093]A preferred method of atomizing is by centrifugal atomizers, also
known as rotary atomizers or spinning-disk atomizers, whereby the molten
mixture is fed onto a rotating surface, where it is caused to spread out
by centrifugal force. The rotating surface may take several forms,
examples of which include a flat disk, a cup, a vaned disk, and a slotted
wheel. The surface of the disk may also be heated to aid in formation of
the cores. Several mechanisms of atomization are observed with flat-disk
and cup centrifugal atomizers, depending on the flow of molten mixture to
the disk, the rotation speed of the disk, the diameter of the disk, the
viscosity of the feed, and the surface tension and density of the feed.
At low flow rates, the molten mixture spreads out across the surface of
the disk and when it reaches the edge of the disk, forms a discrete
droplet, which is then flung from the disk. As the flow of molten mixture
to the disk increases, the mixture tends to leave the disk as a filament,
rather than as a discrete droplet. The filament subsequently breaks up
into droplets of fairly uniform size. At even higher flow rates, the
molten mixture leaves the disk edge as a thin continuous sheet, which
subsequently disintegrates into irregularly sized filaments and droplets.
The diameter of the rotating surface generally ranges from 2 cm to 50 cm,
and the rotation speeds range from 500 rpm to 10,000 rpm or higher,
depending on the desired size of the cores.

[0094]Once the molten mixture has been atomized, the droplets are
congealed, typically by contact with a gas or liquid at a temperature
below the solidification temperature of the droplets. Typically, it is
desirable that the droplets are congealed in less than about 60 seconds,
preferably in less than about 10 seconds, more preferably in less than
about 1 second. The congealing step often occurs in an enclosed space to
simplify collection of the cores. In such cases, the temperature of the
congealing media (either gas or liquid) will increase over time as the
droplets are introduced into the enclosed space. Thus, a cooling gas or
liquid is often circulated through the enclosed space to maintain a
constant congealing temperature.

[0095]The cores are preferably made by a melt-congeal process comprising
the steps of melting the matrix material and dispersing therein any
optional components; and directing the so-formed melt to an atomizing
apparatus, preferably a spinning disk atomizer operating at 1500 to
10,000 rpm, preferably 2500 to 6500 rpm, whereby small droplets of the
melt are formed and radially dispersed by centrifugal force into a
cooling chamber where they rapidly lose heat and congeal into small,
generally spherical particles.

[0096]The resulting melt-congeal cores are generally smooth, round
spheres. The cores may have a volume weighted mean diameter of from 10
microns up to 500 microns. Preferably, the volume weighted mean diameter
of the cores is less than 250 microns, more preferably less than about
150 microns, and even more preferably less than 100 microns. In order to
be amenable to coating, it is preferred that the melt-congeal cores have
a volume-weighted mean diameter of at least about 20 microns. Such small
melt-congeal cores provide faster dissolution of the drug relative to
larger cores with the same drug loading. The inventors have found that
the dissolution rate or release rate of the drug from the solid amorphous
dispersion layer is primarily a function of the ratio of the surface area
of the solid amorphous dispersion layer to the mass of the solid
amorphous dispersion layer. Multiparticulates having a higher ratio of
surface area to mass of the solid amorphous dispersion layer have faster
dissolution rates. Thus, multiparticulates with smaller cores will have a
faster dissolution rate relative to multiparticulates with larger cores
at the same coating thickness of the solid amorphous dispersion layer.
Alternatively, multiparticulates with smaller cores can have higher drug
loadings (that is, the mass of drug per total mass of the
multiparticulate) and still achieve the same dissolution rate as
multiparticulates with larger cores at the same ratio of surface area to
mass of the solid amorphous dispersion layer.

[0097]In addition, when such cores are incorporated into dosage forms that
present the multiparticulates to the mouth, (such as a fast dissolving
dosage form or a sachet), such small multiparticulates may be more
pleasing to patients, since such small multiparticulates present a
smooth, rather than gritty sensation in the mouth, if such
multiparticulates are even felt at all.

Solid Amorphous Dispersion Layer

[0098]The solid amorphous dispersion layer 20 surrounds the core 10 and
comprises a drug and a polymer. By "solid amorphous dispersion" is meant
a material that is solid at 25° C. in which at least a portion of
the drug is in the amorphous form and dispersed in the polymer.

[0099]"Amorphous" refers to material that is not crystalline. It has been
found that for poorly water soluble drugs having poor bioavailability
that bioavailability improves as the fraction of drug present in the
amorphous state in the solid amorphous dispersion layer increases.
Preferably, at least a major portion of the drug in the solid amorphous
dispersion layer is amorphous. As used herein, the term "a major portion"
of the drug means that at least about 60% of the drug in the solid
amorphous dispersion layer is in the amorphous form, as opposed to the
crystalline form; in other words, the amount of drug in crystalline form
does not exceed about 40 wt %. Preferably the drug in the solid amorphous
dispersion layer is "substantially amorphous," meaning that at least
about 75 wt % of the drug in the solid amorphous dispersion layer is
amorphous; in other words, the amount of drug in crystalline form does
not exceed about 25 wt %. Even more preferably, the drug in the solid
amorphous dispersion layer is "almost completely amorphous," meaning that
at least about 90 wt % of the drug in the dispersion is amorphous; in
other words, the amount of drug in the crystalline form does not exceed
about 10 wt %. Amounts of crystalline drug may be measured by Powder
X-Ray Diffraction (PXRD), by Scanning Electron Microscope (SEM) analysis,
by Differential Scanning Calorimetry (DSC), or by any other known
quantitative measurement.

[0100]The amorphous drug can exist as a pure phase, as a solid solution of
drug homogeneously distributed throughout the polymer or any combination
of these states or those states that lie between them. Preferably, at
least a portion of the drug and polymer are present in the form of a
solid solution or molecular dispersion. The solid amorphous dispersion is
preferably "substantially homogeneous" so that the amorphous drug is
dispersed at the molecular level as homogeneously as possible throughout
the polymer. As used herein, "substantially homogeneous" means that the
drug present in relatively pure amorphous domains within the solid
amorphous dispersion layer is relatively small, on the order of less than
about 20 wt %, and preferably less than about 10 wt % of the total amount
of drug in the solid amorphous dispersion layer. Solid amorphous
dispersion layers of the present invention that are substantially
homogeneous generally are more physically stable and have improved
concentration-enhancing properties and, in turn improved bioavailability,
relative to nonhomogeneous dispersions.

[0101]When the drug and the polymer have glass transition temperatures
that differ by more than about 20° C., the fraction of drug
present in relatively pure amorphous drug domains or regions within the
solid amorphous dispersion layer can be determined by measuring the glass
transition temperature (Tg) of the dispersion. Tg as used
herein is the characteristic temperature at which a glassy material, upon
gradual heating, undergoes a relatively rapid (i.e., in 10 to 100
seconds) physical change from a glassy state to a rubbery state. The
Tg of an amorphous material such as a polymer, drug, or solid
amorphous dispersion can be measured by several techniques, including by
a dynamic mechanical analyzer (DMA), a dilatometer, a dielectric
analyzer, and by DSC. The exact values measured by each technique can
vary somewhat, but usually fall within 10° to 30° C. of
each other. When the solid amorphous dispersion exhibits a single
Tg, the amount of drug in pure amorphous drug domains or regions in
the dispersion is generally less than about 10 wt %, confirming that the
dispersion is substantially homogeneous and is a solid solution. This is
in contrast to a simple physical mixture of pure amorphous drug particles
and pure amorphous polymer particles, which generally display two
distinct Tgs, one being that of the drug and the other that of the
polymer. For a solid amorphous dispersion that exhibits two distinct
Tgs, it may be concluded that at least a portion of the drug is
present in relatively pure amorphous domains. Preferably, the solid
amorphous dispersion displays at least one Tg intermediate between
that of pure amorphous drug and pure polymer, indicating that at least a
portion of the drug and polymer are present as a solid solution of drug
molecularly dispersed in the polymer. With DSC, the amount of drug
present in relatively pure amorphous drug domains or regions may be
determined by first measuring the Tg of a substantially homogeneous
dispersion with a known drug loading, to be used as a calibration
standard. From such calibration data, the fraction of drug in relatively
pure amorphous drug domains or regions can be determined. Alternatively,
the amount of drug present in relatively pure amorphous drug domains or
regions may be determined by comparing the magnitude of the heat capacity
(1) that correlates to the drug's Tg with (2) that which correlates
to the Tg of a physical mixture of amorphous drug and polymer.

[0102]The term "polymer" is used conventionally, meaning a compound that
is made of monomers connected together to form a larger molecule. The
polymer should be inert, in the sense that it does not chemically react
with the drug in an adverse manner, and should be pharmaceutically
acceptable. The polymer can be neutral or ionizable, and preferably has
an aqueous-solubility of at least about 0.1 mg/mL over at least a portion
of the pH range of about 1-8. Polymers suitable for use with the present
invention may be cellulosic or non-cellulosic. Of these, ionizable and
cellulosic polymers are preferred, with ionizable cellulosic polymers
being more preferred. By "cellulosic" is meant a cellulose polymer that
has been modified by reaction of at least a portion of the hydroxyl
groups on the saccharide repeating units with a compound to form an ester
or an ether substituent.

[0103]A preferred class of polymers comprises polymers that are
"amphiphilic" in nature, meaning that the polymer has hydrophobic and
hydrophilic portions. The hydrophobic portion may comprise groups such as
aliphatic or aromatic hydrocarbon groups. The hydrophilic portion may
comprise either ionizable or non-ionizable groups that are capable of
hydrogen bonding such as hydroxyls, carboxylic acids, esters, amines or
amides.

[0104]Polymers suitable for forming solid amorphous dispersions include
polyvinylpyrollidone, polyoxyethylene-polyoxypropylene block copolymers
(sold under the trade names PLURONIC and LUTROL), polyacrylates and
polymethacrylates sold under the trade name EUDRAGIT, and ester and ether
substituted cellulosic polymers. One preferred class of polymers is
neutral, amphiphilic polymers such as hydroxypropyl methyl cellulose
(HPMC) and hydroxypropyl methyl cellulose acetate.

[0107]Additional polymers suitable for use in the solid amorphous
dispersion layer are disclosed in US published patent application
2002/0103225, herein incorporated by reference.

[0108]The solid amorphous dispersion layer provides fast dissolution of
the drug, or improves the concentration of dissolved drug in a use
environment relative to a control composition consisting essentially of
the drug alone without any polymer. As used herein, a "use environment"
can be either the in vivo environment of the GI tract, subdermal,
intranasal, buccal, intrathecal, ocular, intraaural, subcutaneous spaces,
vaginal tract, arterial and venous blood vessels, pulmonary tract or
intramuscular tissue of an animal, such as a mammal and particularly a
human, or the in vitro environment of a test solution, such as Phosphate
Buffered Saline (PBS) solution or a Model Fasted Duodenal (MFD) solution.
Concentration enhancement may be determined through either in vitro
dissolution tests or through in vivo tests. It has been determined that
enhanced drug concentration in in vitro dissolution tests in MFD solution
or PBS solution is a good indicator of in vivo performance and
bioavailability. An appropriate PBS solution is an aqueous solution
comprising 20 mM sodium phosphate (Na2HPO4), 47 mM potassium
phosphate (KH2PO4), 87 mM NaCl, and 0.2 mM KCl, adjusted to pH
6.5 with NaOH. An appropriate MFD solution is the same PBS solution
wherein there is also present 7.3 mM sodium taurocholic add and 1.4 mM of
1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine. In particular, a
composition of the present invention may be dissolution-tested by adding
it to MFD or PBS solution and agitating to promote dissolution, or by
performing a membrane permeation test as generally described in this
section and described in detail in the Examples.

[0109]Preferably, when dosed to an aqueous use environment, a composition
of the present invention provides a maximum drug concentration (MDC) that
is at least 1.25-fold the MDC provided by a control composition, e.g., if
the MDC provided by the control composition is 100 μg/mL, then a
composition of the present invention comprising a solid amorphous
dispersion of the drug provides an MDC of at least 125 μg/mL. The
control composition is conventionally the undispersed drug alone such as
the crystalline drug alone in its most thermodynamically stable
crystalline form; in cases where a crystalline form of the drug is
unknown, the control may be amorphous drug alone. The control composition
may also be the drug plus an inert diluent that does not solubilize the
drug. More preferably, the MDC achieved with the compositions of the
present invention are at least 2-fold that of the control composition,
even more preferably at least 3-fold, and most preferably at least
5-fold. Rather surprisingly, the compositions may achieve extremely large
enhancements in aqueous concentration. In some cases, the MDC of very
hydrophobic drugs provided by the compositions of the present invention
are at least 10-fold, at least 50-fold, at least 200-fold, at least
500-fold, to more than 1000-fold that of the control composition.

[0110]Alternatively, the compositions of the present invention provide in
an aqueous use environment a concentration versus time Area Under the
Curve (AUC), for any period of at least 90 minutes between the time of
introduction into the use environment and about 270 minutes following
introduction to the use environment that is at least 1.25-fold that of
the control composition. More preferably, the AUC in the aqueous use
environment achieved with the compositions of the present invention are
at least 2-fold, more preferably at least 3-fold, and most preferably at
least 5-fold that of the control composition. For some hydrophobic drugs,
the compositions may provide an AUC value that is at least 10-fold, at
least 25-fold, at least 100-fold, and even more than 250-fold that of the
control composition.

[0111]Alternatively, the compositions of the present invention, when dosed
orally to a human or other animal, provide an AUC in drug concentration
in the blood plasma or serum (or relative bioavailability) that is at
least 1.25-fold that observed in comparison to the control composition.
Preferably, the blood AUC is at least about 2-fold, more preferably at
least about 3-fold, even more preferably at least about 4-fold, still
more preferably at least about 6-fold, yet more preferably at least about
10-fold, and most preferably at least about 20-fold that of the control
composition.

[0112]Alternatively, the compositions of the present invention, when dosed
orally to a human or other animal, provide a maximum drug concentration
in the blood plasma or serum (Cmax) that is at least 1.25-fold that
observed in comparison to the control composition. Preferably, the
Cmax is at least about 2-fold, more preferably at least about
3-fold, even more preferably at least about 4-fold, still more preferably
at least about 6-fold, yet more preferably at least about 10-fold, and
most preferably at least about 20-fold that of the control composition.
Thus, compositions that meet the in vitro or in vivo performance
criteria, or both, are considered to be within the scope of the
invention.

[0113]A typical in vitro test to evaluate enhanced drug concentration can
be conducted by (1) administering with agitation a test composition (the
multiparticulates) to a test medium; (2) in a separate test, adding an
appropriate amount of control composition (crystalline drug) to an
equivalent amount of test medium; and (3) determining whether the
measured MDC and/or AUC of the test composition in the test medium is at
least 1.25-fold that provided by the control composition. In conducting
such a dissolution test, the amount of test composition and control
composition used is that amount which, if all the drug had dissolved,
would yield a drug concentration of at least 2-fold, more preferably at
least 10-fold, and most preferably at least 100-fold that of the aqueous
solubility or equilibrium concentration of the drug. For some test
compositions of a very poorly water soluble drug, it may be necessary to
administer an even greater amount of the test composition to determine
the MDC.

[0114]MDC and/or AUC are typically determined by measuring the
concentration of dissolved drug as a function of time by sampling the
test medium and plotting drug concentration in the test medium against
time. The MDC is taken to be the maximum value of dissolved drug measured
over the duration of the test. The aqueous AUC is calculated by
integrating the concentration versus time curve over any 90-minute time
period between the time of introduction of the composition into the
aqueous use environment (when time equals zero) and 270 minutes following
introduction to the use environment (when time equals 270 minutes).
Typically, when the composition reaches its MDC rapidly, in say less than
about 30 minutes, the time interval used to calculate AUC is from time
equals zero to time equals 90 minutes. However, if the AUC of a
composition over any 90-minute time period described above meets these
criteria, then the composition is considered to be within the scope of
the invention.

[0115]To avoid drug particulates that would give an erroneous
determination, the test solution is either filtered or centrifuged.
"Dissolved drug" is typically taken as that material that either passes a
0.45 μm syringe filter or, alternatively, the material that remains in
the supernatant following centrifugation. Filtration can be conducted
using a 13 mm, 0.45 μm polyvinylidine difluoride syringe filter sold
by Scientific Resources under the trademark TITAN®. Centrifugation is
typically carried out in a polypropylene microcentrifuge tube by
centrifuging at 13,000 G for 60 seconds. Other similar filtration or
centrifugation methods can be employed and useful results obtained.

[0116]For example, the use of other types of microfilters may yield values
somewhat higher or lower (±10-40%) than that obtained with the filter
specified above, but will still allow identification of preferred
dispersions. It is recognized that this definition of "dissolved drug"
encompasses not only monomeric solvated drug molecules but also a wide
range of species such as polymer/drug assemblies that have submicron
dimensions such as drug aggregates, aggregates of mixtures of polymer and
drug, micelles, polymeric micelles, colloidal particles or nanocrystals,
polymer/drug complexes, and other such drug-containing species that are
present in the filtrate or supernatant in the dissolution test.

[0117]An in vitro membrane permeation test may also be used to evaluate
the compositions of the present invention. Further details of this
membrane permeation test are presented in commonly assigned U.S. Patent
Application Ser. No. 60/557,897, entitled "Method and Device for
Evaluation of Pharmaceutical Compositions," filed Mar. 30, 2004 (attorney
Docket No. PC25968), the disclosure of which is incorporated herein by
reference.

[0118]In general terms, a typical in vitro membrane permeation test to
evaluate enhanced drug concentration can be conducted by providing a
drug-permeable membrane between feed and permeate reservoirs, as
described in detail in the Examples, then (1) administering a sufficient
quantity of test composition (that is, the multiparticulates) to a feed
test medium, such that if all of the drug dissolved, the theoretical
concentration of drug would exceed the equilibrium concentration of the
drug by a factor of at least 2; (2) separately adding an equivalent
amount of control composition to an equivalent amount of feed test
medium; (3) measuring the flux of drug across the membrane from the feed
to the permeate reservoir, and (4) determining whether the measured
maximum flux of drug provided by the test composition is at least
1.25-fold that provided by the control composition. A composition of the
invention provides concentration enhancement if, when administered to an
aqueous use environment, it provides a maximum flux of drug in the above
test that is at least about 1.25-fold the maximum flux provided by the
control composition. Preferably, the maximum flux provided by the
compositions of the invention are at least about 1.5-fold, more
preferably at least about 2-fold, and most preferably at least about
3-fold that provided by the control composition.

[0119]Relative bioavailability or Cmax of drugs in the compositions
of the invention can be tested in vivo in animals or humans using
conventional methods for making such a determination, such as a crossover
study. In an exemplary in vivo crossover study, a test composition
comprising the multiparticulates is dosed to half a group of test
subjects and, after an appropriate washout period (e.g., one week) the
same subjects are dosed with a control composition that consists of an
equivalent quantity of crystalline drug as was dosed with the test
composition, but with no dispersion polymer present. The other half of
the group is dosed with the control composition first, followed by the
test composition. Relative bioavailability is measured as the
concentration of drug in the blood (serum or plasma) versus time AUC
determined for the test group divided by the AUC in the blood provided by
the control composition. Preferably, this test/control ratio is
determined for each subject, and then the ratios are averaged over all
subjects in the study. In vivo determinations of AUC and Cmax can be
made by plotting the serum or plasma concentration of drug along the
ordinate (y-axis) against time along the abscissa (x-axis). To facilitate
dosing, a dosing vehicle may be used to administer the dose. The dosing
vehicle is preferably water, but may also contain materials for
suspending the test or control composition, provided these materials do
not dissolve the composition or change the aqueous solubility of the drug
in vivo. The determination of AUCs is a well-known procedure and is
described, for example, in Welling, "Pharmacokinetics Processes and
Mathematics," ACS Monograph 185 (1986).

Process for Forming the Spray Coated Dispersion Layer

[0120]The solid amorphous dispersion layer is formed by spray-coating a
spray solution of solvent, dissolved drug and dissolved polymer onto the
cores under conditions that result in rapid evaporation of the solvent to
yield a solid amorphous dispersion layer surrounding the core. The spray
solution is atomized into droplets. The fluidized cores are repeatedly
circulated through the droplets. The drying conditions are such that the
solvent in the droplets rapidly evaporates so as to form the solid
amorphous dispersion layer.

[0121]The spray solution comprises the drug and polymer dissolved in a
common solvent. Solvents suitable for spray-coating can be any compound
or mixture of compounds in which the drug and the polymer are mutually
soluble. Preferably, the solvent is also volatile with a boiling point of
150° C. or less. In addition, the solvent should have relatively
low toxicity and be removed from the solid amorphous dispersion to a
level that is acceptable according to The International Committee on
Harmonization (ICH) guidelines. Removal of solvent to this level may
require a subsequent processing step such as tray-drying. Exemplary
solvents include methanol, ethanol, isopropyl alcohol, acetone, ethyl
acetate, acetonitrile, methylene chloride, toluene,
1,1,1-trichloroethane, and tetrahydrofuran. Lower volatility solvents
such as dimethyl acetamide or dimethylsulfoxide can also be used in small
amounts in mixtures with a volatile solvent. Mixtures of solvents, such
as 50% methanol and 50% acetone, can also be used, as can mixtures with
water, so long as the polymer and drug are sufficiently soluble to make
the spray-coating process practicable. Preferred solvents are alcohols,
acetone, and mixtures thereof.

[0122]The amount of drug and polymer in the spray solution depends on the
solubility of each in the spray solution and the desired ratio of drug to
polymer in the resulting solid amorphous dispersion layer. Preferably,
the spray solution comprises at least about 0.01 wt %, more preferably at
least about 0.1 wt %, even more preferably at least about 1 wt %, and
most preferably at least about 10 wt % dissolved solids.

[0123]The spray solution is sprayed onto the cores under conditions that
cause the solvent to evaporate rapidly. The strong driving force for
solvent evaporation is generally provided by maintaining the partial
pressure of solvent in the spray-coating apparatus well below the vapor
pressure of the solvent at the temperature of the drying droplets. This
is accomplished by mixing the liquid droplets with a warm drying gas. In
addition, at least a portion of the heat required for evaporation of
solvent may be provided by heating the spray solution, or by heating the
atomizing gas.

[0124]Generally, the spray solution temperature can range anywhere from
just above the solvents freezing point to about 20° C. above its
ambient pressure boiling point (by pressurizing the solution) and in some
cases even higher. Spray solution flow rates to the spray nozzle can vary
over a wide range depending on the type of nozzle, fluidized bed size and
spray-coating conditions.

[0125]Generally, the energy for evaporation of solvent from the spray
solution in a spray-coating process comes primarily from a drying gas,
which is typically the fluidizing gas. The drying gas can, in principle,
be essentially any gas such as air. For safety reasons and to minimize
undesirable chemical interactions with the drug or other materials in the
solid amorphous dispersion, an inert gas such as nitrogen,
nitrogen-enriched air or argon may be utilized. The drying gas is
typically introduced into the coating chamber at a temperature between
about 20° and about 80° C. and preferably between about
30° and about 70° C. In general, the drying gas is
maintained at a temperature sufficiently low that the cores will not melt
during the spray-coating process. Accordingly, the inlet temperature is
usually maintained at a temperature of at least 10° C. less than
the melt temperature of the core. The atomizing gas temperature may range
from 0 to 80° C. Preferably, the temperature in the coating
chamber is controlled so that the cores do not exceed 50° C.

[0126]The large surface-to-volume ratio of the spray solution droplets
after they impact the cores and the large driving force for evaporation
of solvent leads to rapid solidification times for the droplets after
they impact the cores. Droplet sizes may be less than 100 μm, less
than 50 μm, or less than 20 μm. Solidification times should be less
than about 20 seconds, preferably less than about 10 seconds, and more
preferably less than 1 second. This rapid solidification is often
critical to maintaining a uniform, homogeneous solid amorphous dispersion
layer instead of separating into drug-rich and polymer-rich phases. As
noted above, to obtain large enhancements in concentration and
bioavailability it is often necessary to obtain as homogeneous a
dispersion as possible.

[0127]The atomizer may be any suitable atomizer, such as a two fluid or
three fluid nozzle. While the atomizer may be located at the bottom of
the spray-coating apparatus as described above, the atomizer may
alternatively be placed in the top or side walls of the spraying chamber
and the chamber can be provided with more than one atomizer. It is
however, preferred that the atomizer is provided in the bottom to obtain
a more even and accurate distribution of the spray solution on the cores.
Atomizing pressure is typically 1' to 3 bar.

[0129]In a preferred process for forming the solid amorphous dispersion
layer, a Wurster fluidized bed system is used. In this system, a
cylindrical partition (the Wurster column) is placed inside a conical
product container in the spray-coating apparatus. A fluidizing gas passes
through a distribution plate located at the bottom of the product
container to fluidize the cores, with the majority of the upward moving
gas passing through the Wurster column. An atomizer (such as a nozzle)
located at the bottom of the Wurster column atomizes the solution into
droplets that travel upward. The droplets deposit on the cores entering
the Wurster column as they pass through the droplets. The solvent in the
droplets evaporates as the cores travel up the Wurster column and out
into the drying chamber. The partially coated cores fall down outside of
the Wurster column, where they are fluidized until passing through the
Wurster column again. After repeatedly passing through the Wurster
column, the cores are coated with a layer of solid amorphous dispersion
of the drug and polymer.

[0130]To reduce static charges in order to apply a uniform coating,
humidification of the fluidizing gas is helpful. The dew point is
preferably greater than 15° C., and preferably ranges from
15° C. to 30° C., more preferably from 25° C. to
25° C. The fluidizing gas flow rate is typically 20-60 SCFM. Other
process variables such as design of air distribution plate and Wurster
column height can be adjusted to optimize the quality of the fluidization
and minimize agglomeration.

[0131]Spray-coating continues until a predetermined particle size or
weight is obtained. The determination of the desired particle size or
weight can be conducted in accordance with known classification
procedures. Alternatively a predetermined amount of cores is sprayed with
a predetermined amount of solution to produce the particles with the
desired particle size or weight.

[0132]Following coating, the multiparticulates may stay in the
spray-coating apparatus while fluidized for up to several minutes,
further evaporating solvent from the multiparticulates. The final solvent
content of the multiparticulates should be low, since this reduces the
mobility of the drug in the solid amorphous dispersion layer, thereby
improving its stability. Generally, the solvent content of the solid
amorphous dispersion layer after spray-coating should be less than about
10 wt % and preferably less than about 2 wt %.

[0133]Following spray-coating, the multiparticulates can be dried to
remove residual solvent from the solid amorphous dispersion layer using
suitable drying processes, such as tray drying, vacuum drying, fluid bed
drying; microwave drying, belt drying, rotary drying, and other drying
processes known in the art. Preferred secondary drying methods include
vacuum drying, or tray drying under ambient conditions. To minimize
chemical degradation during drying, drying may take place under an inert
gas such as nitrogen, or may take place under vacuum.

[0134]The average diameter of the multiparticulates after applying the
solid amorphous dispersion layer may range from 20 microns to 3 mm. In a
preferred embodiment, the multiparticulates have an average diameter of
from 30 to 500 microns, more preferably from 40 to 200 microns.

[0135]The amount of drug in the multiparticulates depends on the desired
dose of the drug, the amount of other excipients in the solid amorphous
dispersion layer, and the mass of the cores. Typically, the coating
weight of the solid amorphous dispersion layer ranges from less than 1 wt
% to 90 wt % of the multiparticulate (100*(wt coating/(wt coating+wt
core)). In general, the coating weight of the solid amorphous dispersion
layer in the multiparticulates ranges from about 10 wt % to 60 wt %.

[0136]The thickness of the solid amorphous dispersion layer will depend on
the amount of drug in the multiparticulate, the amount of polymer and
other excipients in the solid amorphous dispersion layer, and the core
weight. In general, the solid amorphous dispersion layer ranges from
about 10 microns to about 150 microns in thickness. Smaller cores are
capable of achieving a thinner solid amorphous dispersion layer at the
same drug loading. For example, for a multiparticulate with a 250 micron
diameter core, a 25 wt % coating ((wt coating/(wt coating+wt core)'100)
results in a solid amorphous dispersion layer thickness of about 14
microns, while a multiparticulate with a 1 mm diameter core with the same
coating weight results in a solid amorphous dispersion layer thickness of
about 54 microns. In one embodiment, the solid amorphous dispersion layer
may be less than 30 microns, less than 25 microns, less than 20 microns,
or even less than 15 microns thick.

The Drug

[0137]The drug in the drug layer 20 is a "poorly water soluble drug,"
meaning that the drug has an aqueous solubility of less than about 10
mg/mL at pH 6-7. The drug may have an even lower aqueous solubility, such
as less than about 5 mg/mL, less than about 1 mg/mL, less than about 0.5
mg/mL, less than about 0.1 mg/mL, and even less than about 0.05 mg/mL. A
useful measure of the solubility of poorly water soluble drugs is a
dose-to-aqueous solubility ratio, which may be calculated by dividing the
dose (in mg) by the aqueous solubility (in mg/mL). In general, it may be
said that drugs useful in the invention have a dose-to-aqueous solubility
ratio greater than about 10 mL, and more typically greater than about 100
mL, where the aqueous solubility in mg/mL is the minimum value observed
in an aqueous solution at pH 6-7, and the dose is in mg.

[0140]The optional drug which may be incorporated into the core is not
limited, and may be the same or different than the drug in the drug layer
20. The drug in the core may be a poorly water soluble drug.

Exterior Coating

[0141]Following spray-coating of the solid amorphous dispersion layer, the
multiparticulates may optionally be coated with an additional exterior
coating. FIG. 4 is a cross-sectional schematic of another alternative
embodiment comprising a multiparticulate 4 having an exterior coating 40
surrounding the solid amorphous dispersion layer 20. The exterior coating
40 may be any conventional coating, such as a protective film coating, a
coating to provide delayed or sustained release of the drug from the
solid amorphous dispersion layer 20, or to provide tastemasking. The
exterior coating is applied under conditions that minimize changes to the
solid amorphous dispersion layer.

[0142]In one embodiment, the coating 40 is an enteric coating to provide
delayed release of the drug. By "enteric coating" is meant an acid
resistant coating that remains intact and does not dissolve at pH of less
than about 4. The enteric coating surrounds the multiparticulate so that
the solid amorphous dispersion layer does not dissolve or erode in the
stomach. The enteric coating may include an enteric coating polymer.
Enteric coating polymers are generally polyacids having a pKa of
about 3 to 5. Examples of enteric coating polymers include: cellulose
derivatives, such as cellulose acetate phthalate, cellulose acetate
trimellitate, hydroxypropyl methyl cellulose acetate succinate, cellulose
acetate succinate, carboxy methyl ethyl cellulose, methylcellulose
phthalate, and ethylhydroxy cellulose phthalate; vinyl polymers, such as
polyvinyl acetate phthalate, vinyl acetate-maleic anhydride copolymer,
polyacrylates; and polymethacrylates such as methyl acrylate-methacrylic
acid copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer;
and styrene-maleic mono-ester copolymer. These may be used either alone
or in combination, or together with other polymers than those mentioned
above.

[0143]One class of preferred enteric coating materials are the
pharmaceutically acceptable methacrylic acid copolymer which are
copolymers, anionic in character, based on methacrylic acid and methyl
methacrylate. Some of these polymers are known and sold as enteric
polymers, for example having a solubility in aqueous media at pH 5.5 and
above, such as the commercially available EUDRAGIT enteric polymers, such
as Eudragit L 30, a polymer synthesized from dimethylaminoethyl
methacrylate and Eudragit S. One preferred enteric coating solution
consists of about 40 wt % Eudragit L30-D55 and 2.5 wt % triethylcitrate
in about 57.5 wt % water.

[0144]FIG. 5 is a cross-sectional schematic of another embodiment
comprising a swelling agent 18 in the core 10 of the multiparticulate 5
and surrounded by an exterior coating 50 that is a water permeable,
drug-impermeable exterior coating. The multiparticulate delivers drug by
imbibing water through the coating 50. The core 10 may also include an
optional dissolution enhancer 18 distributed throughout the matrix
material 12. When placed in an aqueous fluid-containing environment such
as a mouth or gastric environment, the multiparticulate permits aqueous
fluid to pass through the coating 50 into the core 10. The imbibed
aqueous fluid comes into contact with swelling agent 16, causing the same
to swell and eventually cause rupture of the coating 50. In addition, the
optional dissolution enhancer dissolves and leaves the core, leaving
behind pores or channels that allow rapid diffusion of water into the
core to increase the rate of water uptake by the swelling agent.

[0145]When the exterior coating 50 is used to provide tastemasking, the
coating and core constituents are chosen so that the rupture is
sufficiently delayed in time, for most or all of the multiparticulates,
so that the coating ruptures in the stomach of a patient, rather than in
the mouth. Multiparticulate rupture times may vary from about 1 to about
30 minutes, with substantially all of the multiparticulates in a given
dose ruptured within one hour. In this fashion, virtually all of the drug
is released well after the multiparticulates have passed through the
mouth.

[0146]The coating 50 preferably comprises a water-permeable, substantially
drug-impermeable polymer capable of permitting imbibition of aqueous
fluid in a mouth or gastric environment. Given the high surface to volume
ratio of the small multiparticulates, the coatings may have relatively
low water permeability and still be appropriate. This is particularly
true when long lag times prior to rupture are desired. The coating has a
low drug permeability to minimize drug release into the mouth or buccal
use environment when the coating is intact. An important property of the
coating is that it has sufficiently low ductility and tensile strength
that it ruptures when the core swells rather than merely expanding with
the core. Thus, preferred materials are those which produce coatings with
elongation at break in the range of 10 to 30%. Materials with elongation
at break values greater than about 30% often will only stretch when the
core expands, rather than rupture. For many polymers, the proper
molecular weight is a key property. If molecular weight is too high, the
polymer may form a coating that is too strong or too elastic to rupture.
For example, low-density polyethylene is likely too elastic and strong;
however, a lower molecular weight form, such as some microcrystalline
waxes, may be weak enough that they easily rupture. Also, morphology is
an important property. Coatings can be weakened by making them
semi-porous or grainy such that there is poor bonding between adjacent
polymer domains. Addition of incompatible additives can also weaken the
coating, allowing rupture. The coating should not be highly porous; or
else the swelling pressure may be relieved or drug may escape prior to
rupture. An additional property of the coating when used with compressed
dosage forms such as chewable tablets is that it is sufficiently strong
and ductile to resist damage during compaction.

[0147]In order to provide taste masking, coating materials should either
be substantially water-insoluble, meaning a solubility in water at
ambient temperature of less than 0.1 mg/ml, or should have sufficiently
slow dissolution in water so that the coating ruptures prior to
dissolution of a significant portion of the coating. Preferred
water-insoluble coatings include: cellulose ethers such as ethyl
cellulose; cellulose esters such as cellule acetate, cellulose acetate
butyrate, cellulose triacetate, and cellulose acetate propionate;
potyacrylates; and polymethacrylates. A particularly preferred cellulose
ether is ethyl cellulose (commercially available as SURELEASE from
Colorcon of West Point, Pennsylvania). A particularly preferred
polymethycrylate is a 2:1 copolymer of ethyl acrylate and methyl
methacrylate (commercially available as EUDRAGIT NE from Rohm Pharma of
Darmstadt, Germany). An exemplary coating solution using Eudragit NE30D
contains 12.5% poly (ethyl acrylate, methyl methacrylate), 10% talc, and
77.5% water. The composition of the final dry coating (water removed) is
55% poly (ethyl acrylate, methyl methacrylate), and 45% talc.

[0149]Exterior coatings can be formed using solvent-based and hot-melt
coating processes. In solvent-based processes, the coating is made by
first forming a solution or suspension comprising the solvent, the
coating material and optional coating additives. The coating materials
may be completely dissolved in the coating solvent, or only dispersed in
the solvent as an emulsion or suspension or a combination of the two.
Latex dispersions are an example of an emulsion or suspension that may be
useful as in a solvent-based coating process. In one aspect, the solvent
is a liquid at room temperature.

[0150]Coating may be conducted by conventional techniques, such as by pan
coaters, rotary granulators and fluidized bed coaters such as top-spray,
tangential-spray or bottom-spray (Wurster coating), most preferably the
latter. A top-spray method can also be used to apply the coating. In this
method, coating solution is sprayed down onto the fluidized cores. The
solvent evaporates from the coated cores and the coated cores are
re-fluidized in the apparatus. Coating continues until the desired
coating thickness is achieved.

[0151]The coating may also be applied using a hot-melt coating technique.
In this method, the coating excipients and additives are first melted and
then sprayed onto the cores. Typically, the hot-melt coating is applied
in a fluidized bed equipped with a top-spray arrangement.

[0152]Another method for applying a hot-melt coating to the cores is to
use a modified melt-congeal method. In this method, the cores are
suspended in the molten coating excipients, the melting point of the
cores being greater than the melting point of the coating excipients.
This suspension is then formed into droplets comprising the cores
surrounded by the coating excipients. The droplets are typically formed
by an atomizer, such as a rotary or spinning-disk atomizer. The droplets
are then cooled to congeal the coating, forming the coated
multiparticulates.

[0153]The exterior coating is present in a sufficient amount to slow or
delay the release of drug. The exterior coating may range in an amount of
from 5 to 60 wt % of the mass of the multiparticulates (100*(wt exterior
coating/wt multiparticulate)).

Dosage Forms

[0154]The multiparticulates may be administered using any known dosage
form. Exemplary oral dosage forms include: powders or granules; tablets;
chewable tablets; capsules; unit dose packets, sometimes referred to in
the art as "sachets" or "oral powders for constitution" (OPC); syrups;
and suspensions. When the dosage form is an OPC, syrup, suspension or the
like, in which the multiparticulate is suspended in a liquid when
administered to the patient, the dosage form is administered to the
patient sufficiently quickly so that the multiparticulates do not
prematurely release the dosage form or the patient's mouth.

[0155]Conventional formulation excipients may be employed in the
compositions of this invention, including those excipients well-known in
the art. Generally, excipients such as fillers, disintegrating agents,
pigments, binders, lubricants, glidants, flavorants, and so forth may be
used for customary purposes and in typical amounts without adversely
affecting the properties of the compositions. These excipients may be
utilized after the multiparticulate compositions have been formed, in
order to formulate the compositions into tablets, capsules, suspensions,
powders for suspension, and the like.

[0162]Examples of glidants include silicon dioxide, talc and cornstarch.

[0163]One preferred dosage form is a capsule that may be filled with the
multiparticulates.

[0164]Chewable tablets for oral administration are another preferred
dosage form. Such a dosage form may be formed by combining the
multiparticulates with compressible sugar, a filler such as
microcrystalline cellulose, a disintegrant, and flavorants. To reduce the
risk of breaking the coating of the multiparticulates, soft excipients or
excipients with small particle sizes may be used. These ingredients may
be mixed together followed by addition of a lubricant such as magnesium
stearate, followed by further mixing, followed by compression.

[0165]Without further elaboration, it is believed that one of ordinary
skill in the art can, using the foregoing description, utilize the
present invention to its fullest extent. Therefore, the following
specific embodiments are to be construed as merely illustrative and not
restrictive of the scope of the invention. Those of ordinary skill in the
art will understand that variations of the conditions and processes of
the following examples can be used.

EXAMPLES

Attrition Comparison

[0166]This example demonstrates that melt-congeal cores experience less
attrition during the spray-coating process than sucrose cores.

[0167]First, melt-congeal cores comprising 100 wt % gylercyl behenate
(COMPRITOL 888®, a mixture of glycerol mono-, di- and tri-behenates,
available from Gaffe Fosse, Paramus, N.J.) were prepared as follows. The
COMPRITOL was delivered to a B&P 27-mm twin-screw extruder at a rate of
250 g/min. The extruder temperature was maintained at about 93° C.
The material was then pumped using a 2.4 cc Zenith gear pump (located
inside a 95° C. hot box) to the center of a 4-inch diameter
spinning-disk atomizer to form multiparticulates. The surface of the
spinning disk atomizer was maintained at 90° C. while making the
multiparticulates, and the disk was rotating at 3000 rpm. The particles
formed by the spinning-disk atomizer were congealed in ambient air and
collected. The cores were sieved to obtain a fraction with a size range
of 180-250 μm.

[0168]Sucrose cores (6080 sugar spheres, NF, available from Paulaur Corp.,
Cranbury, N.J.) were sieved to obtain a fraction with a size range of
180-250 μm.

[0169]To compare core attrition during the spray-coating process, the
melt-congeal cores and sucrose cores were each separately evaluated by
placing samples of each in a fluid bed coater operated at typical
spray-coating conditions. For these tests, a 100 g sample of each
respective sample was placed in a Mini-Glatt fluid bed coater with a
Wurster column. The inlet temperature was 30° C., atomizing air
pressure was 2 bar (nozzle used without coating solution), and fluidizing
gas flow rate was 26.4 cfm. Samples of the coated cores were withdrawn
from a sample port at regular 15 minute intervals. Samples were evaluated
using optical microscopy. The percent attrition observed (weight of
particles <180 μm) is shown in Table 1. After 60 minutes, the
melt-congeal cores showed 12.5 wt % attrition, while the sucrose cores
showed 50 wt % attrition.

[0170]These examples disclose multiparticulates of the embodiment of FIG.
1 comprising melt-congeal cores and solid amorphous dispersion layers.
The inventors found that by decreasing the dispersion coating and
maintaining a constant melt-congeal core size, the increasing ratio of
surface area to coating mass results in increasing drug release rate.

[0171]First, melt-congeal cores comprising 100 wt % COMPRITOL 888®
were prepared as follows. The COMPRITOL was added to a sealed, jacketed
stainless-steel tank. Heating fluid at 90° C. was circulated
through the jacket of the tank, and the COMPRITOL was melted and stirred.
The COMPRITOL feed solution was pumped at a rate of about 100 g/min using
a Zenith gear pump to the center of a 4-inch diameter spinning-disk
atomizer rotating at 10,000 rpm, the surface of which was heated to
90° C. The particles formed by the atomizer were congealed in
ambient air and collected. The cores were sieved to obtain a fraction
with a size range of 63-75 μm.

[0172]Next, a solid amorphous dispersion containing 50 wt % celecoxib and
50 wt % HPMCAS (AQOAT-MG from Shin Etsu, Tokyo, Japan) was coated onto
the melt congeal cores as follows. A solution was formed containing 158.9
g celecoxib (5 wt %), 158.9 g HPMCAS (5 wt %), 2701.0 g acetone (85 wt
%), and 158.9 g water (5 wt %). The solution was sprayed onto 120 g of
the melt congeal cores in a Mini-Glatt fluid bed coater with a Wurster
column. The spray solution was pumped into the fluid bed coater at a rate
of 3.5 g/min. The inlet temperature was 35° C., atomizing air
pressure was 2 bar, and fluidizing gas flow rate was 22.5 cfm. The solid
amorphous dispersion layer was applied until a coating weight of 23.2 wt
% was achieved (coating 25 wt/coating plus core wt). 56.3 g of the
so-coated cores were removed from the fluid bed coater, and set aside as
the multiparticulates for Example 1. A sample of the coated cores of
Example 1 was observed by SEM analysis and the approximate average
diameter was about 90 μm. The surface area per gram of coating was
25×104 mm2/g.

[0173]The multiparticulates remaining in the fluid bed coater were further
coated, until a coating weight for the solid amorphous dispersion layer
of 52.4 wt % was achieved. 61.3 g of coated cores were removed from the
fluid bed coater, and set aside as the multiparticulates of Example 2.
The approximate average size of the dispersion-coated cores as determined
by SEM analysis was about 130 μm. The surface area per coating weight
was 9.4×104 mm2/g.

[0174]An additional sample of 90.2 g coated cores was removed from the
fluid bed coater after a coating weight for the solid amorphous
dispersion layer of 75.0 wt % was achieved. Finally, after a solid
amorphous dispersion layer of 87.1 wt % was achieved, 186.5 g of coated
cores were removed from the fluid bed coater, and set aside as the
multiparticulates of Example 3. The approximate average size of the
dispersion-coated cores as determined by SEM analysis was about 230
μm. The surface area per gram of coating was 4.1×104
mm2/g.

Celecoxib Release from Multiparticulates of Examples 1-3

[0175]The rate of release of celecoxib in vitro from multiparticulates of
Examples 1-3 was determined using the follow procedure. A sample of the
multiparticulates were placed into a USP Type 2 dissoette flask equipped
with Teflon-coated paddles rotating at 100 rpm. A sufficient amount of
the multiparticulates was added to provide about 400 mg of celecoxib. The
flask contained 900 mL of simulated mouth buffer (KH2PO4
buffer, pH 7.3, with 0.5 wt % polysorbate 80 (sold as Tween® 80,
available commercially from ICI)) at 37.0±0.5° C. Samples were
taken using a syringe attached to a cannula with a 70 μm filter. A
sample of the fluid in the flask was drawn into the syringe, the cannula
was removed, and a 0.45-μm filter was attached to the syringe. One mL
of sample was filtered into a High Performance Liquid Chromatography
(HPLC) vial. Samples were collected at 0, 5, 10, 20, 30, 60, 90, and 120
minutes following addition of the multiparticulates to the flask. The
samples were analyzed using HPLC (Zorbax SB-C8 column, 3.5 μm
particles, 7.5 cm×4.6 mm i.d.; 45/55 5 mM triethanolamine, pH
7.0/acetonitrile at 1.5 mL/min; absorbance measured at 254 nm with a
diode array spectrophotometer).

[0176]The amount of drug released was calculated based on the potency
assay of the formulation. To measure the potency of the
multiparticulates, about 2 mg of the multiparticulates were weighed and
added to a 10 mL volumetric flask. Next, about 8 mL methanol was added,
and the solution was sonicated for 20 minutes. The flask was cooled to
room temperature and filled to volume with methanol. An aliquot of the
solution was then centrifuged for 5 minutes at 13,000 rpm, and analyzed
to determine the total amount of drug in the formulation. The potency
assay of the formulation was used to calculate the amount of drug added
for each dissolution test. The amount of drug in each sample was divided
by the total amount of drug added for the test, and the results are
reported as percent of assay. The results of these dissolution tests are
given in Table 2.

[0177]The results in Table 2 show that as the dispersion coating is
decreased for a given core size, the surface area per coating weight
increases, and drug release rate is increased. For Example 1, the surface
area per gram of coating was 25×104 mm2/g, while the
surface area per gram of coating for Examples 2 and 3 was
9.4×104 mm2/g and 4.1×104 mm2/g
respectively. Example 1 had the fastest release rate, followed by
Examples 2 and 3 respectively.

Example 4

[0178]This example discloses a multiparticulate of the embodiment of FIG.
1 comprising a melt-congeal core and a solid amorphous dispersion layer.
This example demonstrates that multiparticulates with small cores can
achieve equivalent drug release rates with higher drug loading relative
to multiparticulates made from larger cores made from sugar spheres.

[0179]First, melt-congeal cores were prepared as in Example 1. The cores
were sieved to obtain a fraction with a size range of 83-75 μm.

[0180]Next, a solid amorphous dispersion containing 50 wt % celecoxib and
50 wt % HPMCAS-LG was coated onto the melt congeal cores as follows. A
solution was formed containing 62.5 g celecoxib (5 wt %), 62.5 g HPMCAS
(5 wt %), 1061.7 g methanol (85 wt %), and 62.5 g water (5 wt %). The
solution was sprayed onto 120 g of the melt congeal cores in a Mini-Glatt
fluid bed coater with a Wurster column, and aliquots of the coated cores
were periodically removed. The spray solution was pumped into the fluid
bed coater at a rate of 3 g/min. The inlet temperature was 36° C.,
atomizing air pressure was 2 bar, and fluidizing gas flow rate was 23
cfm. After 84.0 wt % dispersion had been added (dispersion wt/dispersion
plus core wt), the spray solution flow was discontinued, and the
dispersion-coated cores were dried for 2 minutes with the fluidizing gas.
SEM analysis showed that the average size of the dispersion-coated cores
was about 150 μm. The surface area per coating weight was
5.8×104 mm2/g. The drug loading was 42 wt %.

Control 2

[0181]The multiparticulates of Control 2 comprised a sucrose core and a
solid amorphous dispersion layer.

[0182]Sucrose cores (SUGLETS®, NP Pharm, Bazainville, France) (sucrose
and maize starch spheres) with an average size of about 125 μm were
coated with a solid amorphous dispersion containing 50 wt % celecoxib and
50 wt % HPMCAS-LG as follows. A solution was formed containing 60 g
celecoxib (5 wt %), 60 g HPMCAS (5 wt %), and 1078 g methanol (90 wt %).
The solution was sprayed onto 80 g of the cores in a Mini-Glatt fluid bed
coater with a Wurster column. The spray solution was pumped into the
fluid bed coater at a rate of 2-4 g/min. The inlet temperature was
33-35° C., atomizing air pressure was 2 bar, and fluidizing gas
flow rate was 30-32 cfm. After 54.1 wt % dispersion had been added
(dispersion wt/dispersion plus core wt), the spray solution flow was
discontinued, and the dispersion-coated cores were dried for 2 minutes
with the fluidizing gas. Following coating, the multiparticulates were
placed in a 40° C. convection oven overnight for additional
drying. The average size of the dispersion-coated cores was about 195
μm by SEM. The surface area per coating weight was 5.4×104
mm2/g. The drug loading was 27 wt %.

Control 3

[0183]The multiparticulates of Control 3 comprised a sucrose core and a
solid amorphous dispersion layer.

[0184]Sucrose cores (Nu-Core®, available from Chr. Hansen, Inc.,
Milwaukee, Wis.) with an average size of about 300 μm were coated with
a solid amorphous dispersion containing 50 wt % celecoxib and 50 wt %
HPMCAS-LG as described above for Control 1. The spray solution contained
celecoxib, HPMCAS, methanol, and water in a ratio of 5/5/85/5. The
solution was sprayed onto the cores in a Mini-Glatt fluid bed coater with
a Wurster column to obtain a coating weight of 22 wt % (dispersion
wt/dispersion plus core wt). The average size of the dispersion-coated
cores was about 350 μm by SEM. The surface area was 6.5×104
mm2/g coating. The drug loading was 11 wt %.

[0185]The dispersion-coated cores were analyzed using powder x-ray
diffraction (PXRD), and compared to crystalline celecoxib and sucrose
cores alone. The crystalline peaks found in the dispersion-coated cores
corresponded to the crystalline peaks found in the sucrose cores, and not
to the crystalline peaks in the celecoxib alone, indicating that the
celecoxib in the dispersion-coated cores was amorphous.

Celecoxib Release from Multiparticulates of Example 4

[0186]The rate of release of celecoxib in vitro from multiparticulates of
Example 4, and the multiparticulates of Controls 2 and 3, was determined
as described above. Results are shown below in Table 3.

[0187]The results in Table 3 show that the release rate of celecoxib from
the multiparticulates of Example 4 was similar to that of Controls 2 and
3, with the multiparticulates of Example 4 releasing drug a little more
rapidly than Controls 2 and 3. However, Example 4 had a significantly
higher drug loading of 42 wt %, as compared with 27 wt % and 11 wt % for
Controls 2 and 3 respectively. These results show that the smaller cores
of the present invention allow a higher drug loading to be achieved for a
given release rate compared with multiparticulates made from larger cores
while still attaining release rates that are similar to those provided by
multiparticulates with larger cores.

Example 5

[0188]This example discloses a multiparticulate of the embodiment of FIG.
5 comprising a melt-congeal core, a solid amorphous dispersion layer, and
an exterior coating.

[0189]First, melt-congeal cores comprising 60 wt % COMPRITOL 888® (the
matrix material), 35.0 wt % croscarmellose sodium (ACDISOL from FMC of
Philadelphia, Pa.)(swelling agent), and 5 wt % of poloxamer (PLURONIC
F127 from BASF of Mount Olive, N.J.)(dissolution enhancer) were prepared
using the following procedure. The COMPRITOL and the PLURONIC were added
to a sealed, jacketed stainless-steel 1 L tank equipped with a mechanical
mixing paddle. Heating fluid was circulated through the jacket of the
tank. After about 14 minutes, the mixture had melted, having a
temperature of about 93° C. The ACDISOL was added to the melt and
mixed for 5 minutes, resulting in a molten feed. The molten feed was
pumped using a gear pump (Zenith Pump, Parker Hannifin Corp, Model
C-9000, 2.4 cc/rev) to the center of a 4-inch diameter spinning-disk
atomizer, the surface of which was heated to 90° C. The disk was
spinning at 5,000 rpm. The particles formed by the spinning-disk atomizer
were congealed in ambient air and collected. A sample of the melt-congeal
cores was observed by SEM analysis and the approximate average diameter
of the melt-congeal cores was determined to be about 230 μm.

[0191]The multiparticulates were then coated with an exterior coating as
follows. A spray solution was prepared by diluting an aqueous
ethylcellulose dispersion, SURELEASE® E-7-7050 (available from
Colorcon as an aqueous emulsion containing 25 wt % solids) to 15 wt %
solids in water. The solution was sprayed onto 50 g of the
dispersion-coated cores in a Mini-Glatt fluid bed coater with a Wurster
column. The spray solution was pumped into the fluid bed coater at a rate
of 3.6 g/min. The inlet temperature was 59° C., atomizing air
pressure was 2.2 bar, and fluidizing gas flow rate was 25 cfm. After 22.7
wt % exterior coating had been added (dispersion wt/dispersion plus core
wt), the spray solution flow was discontinued, and the coated
multiparticulates were dried for 5 minutes with the fluidizing gas. SEM
analysis showed that the diameter was about 310 μm.

Vakiecoxib Release from Multiparticulates of Example 5

[0192]The rate of release of valdecoxib in vitro from multiparticulates of
Example 5 was determined using the following procedure. About 220 mg of
the multiparticulates of Example 5 were placed into a USP Type 2
dissoette flask equipped with Teflon-coated paddles rotating at 100 rpm.
The flask contained 900 mL of simulated mouth buffer (KH2PO4
buffer, pH 7.3, with 0.5 wt % polysorbate 80 (sold as Tween® 80,
available commercially from ICI)) at 37.0±0.5° C. Samples were
taken using a syringe attached to a cannula with a 70 μm filter. A
sample of the fluid in the flask was drawn into the syringe, the cannula
was removed, and a 0.45-μm filter was attached to the syringe. One mL
of sample was filtered into a High Performance Liquid Chromatography
(HPLC) vial. Samples were collected at 0, 1, 2, 3, 5, 10, 20, 30, and 60
minutes following addition of the multiparticulates to the flask. The
samples were analyzed using HPLC (Zorbax SB-C8 column, 3.5 μm
particles, 7.5 cm×4.6 mm i.d.; 55/45 5 mM triethanolamine, pH
7.0/acetonitrile at 1.5 mL/min; absorbance measured at 256 nm with a
diode array spectrophotometer).

[0193]The amount of drug released was calculated based on the potency
assay of the formulation. To measure the potency of the multiparticulates
of Example 5, about 80 mg of the multiparticulates were weighed and added
to a 25 mL volumetric flask. Next, about 10 mL acetonitrile/methanol
(80/20 vol/vol) was added, and the solution was sonicated for 15 minutes.
The flask was cooled to room temperature and filled to volume with
acetonitrile/methanol (80/20 vol/vol). An aliquot of the solution was
then centrifuged for 5 minutes at 13,000 rpm, and analyzed to determine
the total amount of drug in the formulation. The potency assay of the
formulation was used to calculate the amount of drug added for each
dissolution test. The amount of drug in each sample was divided by the
total amount of drug added for the test, and the results are reported as
percent of assay. The results of these dissolution tests are given in
Table 4.

[0194]The results in Table 4 show release of valdecoxib from the
multiparticulates, following an initial delay.

Examples 6-9

[0195]These examples disclose multiparticulates of the embodiment of FIG.
1 comprising melt-congeal cores and solid amorphous dispersion layers
with a third drug,
[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-
-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester,
also known as torcetrapib. For Examples 6-9, the dispersion coating
weight was varied on melt-congeal cores of a constant size. The
increasing ratio of surface area to coating mass (decreasing dispersion
coating weight) resulted in increasing drug release rate.

[0196]First, melt-congeal cores were prepared as in Example 1. The cores
were sieved to obtain a fraction with a size range of 75-106 μm.

[0197]Next, a solid amorphous dispersion containing 25 wt % torcetrapib
and 75 wt % HPMCAS-MG was coated onto the melt congeal cores as follows.
A solution was formed containing 3 wt % torcetrapib, 9 wt % HPMCAS, and
88 wt % acetone. The solution was sprayed onto 55 g of the melt congeal
cores in a Mini-Glatt fluid bed coater with a Wurster column. The spray
solution was pumped into the fluid bed coater at a rate of 2.5 g/min. The
inlet temperature was 33° C., atomizing air pressure was 2.2 bar,
and fluidizing gas flow rate was 21.9 cfm. The solid amorphous dispersion
layer was applied until a coating weight of about 10 wt % was achieved
(coating wt/coating plus core wt). 8.4 g of the so-coated cores were
removed from the fluid bed coater, and set aside as the multiparticulates
for Example 6. The approximate average size of the dispersion-coated
cores as determined by SEM analysis was about 90 μm. The surface area
per gram of coating was 6.7×104 mm2/g.

[0198]The multiparticulates remaining in the fluid bed coater were further
coated, until a coating weight for the solid amorphous dispersion layer
of about 30 wt % was achieved. 8 g of coated cores were removed from the
fluid bed coater, and set aside as the multiparticulates of Example 7.
The approximate average size of the dispersion-coated cores as determined
by SEM analysis was about 100 μm. The surface area per coating weight
was 6.0×104 mm2/g.

[0199]The multiparticulates remaining in the fluid bed coater were further
coated, until a coating weight for the solid amorphous dispersion layer
of about 50 wt % was achieved. 38.2 g of coated cores were removed from
the fluid bed coater, and set aside as the multiparticulates of Example
8. The volumetric mean particle size of a sample of the coated cores of
Example 8 was determined using the Malvern Mastersizer 2000 particle size
analyzer, and the average diameter was 109 μm. The surface area per
coating weight was 5.5×104 mm2/g.

[0200]Finally, after a solid amorphous dispersion layer of about 75 wt %
was achieved, all remaining coated cores were removed from the fluid bed
coater, and set aside as the multiparticulates of Example 9. The
volumetric mean particle size of a sample of the coated cores of Example
9 was determined using the Malvern particle size analyzer, and the
average diameter was 138 μm. The surface area per coating weight was
4.3×104 mm2/g.

Control 4

[0201]The multiparticulates of Control 4 comprised a sucrose core and a
solid amorphous dispersion layer.

[0202]Sucrose cores (3035, Paulaur Corp., Cranbury, New Jersey) with an
average size of about 600 μm were coated with a solid amorphous
dispersion containing 25 wt % torcetrapib and 75 wt % HPMCAS-MG as
described above. The solid amorphous dispersion layer was applied until a
coating weight of about 10 wt % was achieved (coating wt/coating plus
core wt). The volumetric mean particle size of a sample of the coated
cores of Control 4 was determined using the Malvern particle size
analyzer, and the average diameter was 649 μm. The surface area per
coating weight was 0.92×104 mm2/g.

Torcetrapib Release from Multiparticulates of Examples 6-9

[0203]The rate of release of torcetrapib in vitro from multiparticulates
of Examples 6-9, and Control 4, was determined using the follow
procedure. A sample of the multiparticulates was placed into a USP Type 2
dissoette flask equipped with Teflon-coated paddles rotating at 100 rpm.
A sufficient amount of the multiparticulates was added to provide about
100 μg/mL of torcetrapib. The flask contained buffer solution (6 mM
KH2PO4, 30 mM NaCl, 60 mM KCl, pH 6.8, with 2 wt % polysorbate
80 (sold as Tween® 80, available commercially from ICI)) at
37.0±0.5° C. Samples were taken using a syringe attached to a
cannula with a 10 μm filter. A sample of the fluid in the flask was
drawn into the syringe, the cannula was removed, and a 0.45-μm fitter
was attached to the syringe. One mL of sample was filtered into a High
Performance Liquid Chromatography (HPLC) vial. Samples were collected at
0, 5, 10, and 20 minutes following addition of the multiparticulates to
the flask. The samples were analyzed using HPLC (Waters Symmetry C8
column, 17/83 0.2% H3PO4/methanol, absorbance measured at 256
nm with a diode array spectrophotometer).

[0204]The amount of drug released was calculated based on the potency
assay of the formulation. To measure the potency of the
multiparticulates, a sufficient amount of the multiparticulates were
weighed and added to a 10 mL volumetric flask to obtain approximately 100
μg/mL torcetrapib. Next, the flask was filled to volume with methanol,
and stirred overnight. An aliquot of the solution was then filtered using
a 0.45-μm filter, and analyzed to determine the total amount of drug
in the formulation. The potency assay of the formulation was used to
calculate the amount of drug added for each dissolution test. The amount
of drug in each sample was divided by the total amount of drug added for
the test, and the results are reported as percent of assay. The results
of these dissolution tests are given in Tables 5 and 6.

[0205]The results in Table 5 show generally that as the dispersion coating
is increased for a given core size, the surface area per coating weight
decreases, and initial drug release rate is decreased.

[0207]The results in Table 8 show that increasing core size with a
constant coating weight decreases the surface area per coating weight,
and initial drug release rate is decreased. For Example 8, the surface
area per gram of coating was 6.7×104 mm2/g, while the
surface area per gram of coating for Control 4 was 0.92×104
mm2/g. Example 6 showed faster initial drug release than Control 4.

[0208]The terms and expressions which have been employed in the foregoing
specification are used therein as terms of description and not of
limitation, and there is no intention in the use of such terms and
expressions of excluding equivalents of the features shown and described
or portions thereof, it being recognized that the scope of the invention
is defined and limited only by the claims which follow.